The basic concepts which led to the clinical procedure of guided tissue regeneration were reported by Melcher in 1976 in the Journal of Periodontics. This work identified four distinct connective tissue cell phenotypes in the periodontium; the gingival corium, periodontal ligament, cementum and bone. Melcher proposed that the healing response that occurs after wounding is dependent on the phenotype of cells that repopulate the area. With the knowledge that epithelial cells from the gingival soft tissues would proliferate at a faster rate than bone or periodontal ligament cells, the early efforts at guided tissue regeneration focused on epithelial exclusion by various mechanical means, including the placement of a thin sheet of biocompatible material between the bone defect and overlying soft tissue. Histological evaluation of animal tissues confirmed the hypothesis that if the more aggressive and faster growing gingival epithelial cells were prevented from entering a periodontal bone defect during the healing phase, then new cementum, bone, and periodontal ligament would be formed from undifferentiated mesenchymal cells originating from the adjacent bone, cementum and bone marrow would selectively repopulate the defect.
At present, there is significant interest in the repair and regeneration of bony defects that may result from surgery such as the removal of cysts, the removal of tooth roots, bone loss from infection or inflammatory process around teeth or dental implants, bone atrophy, trauma, tumors or congenital defects. Bone loss may result in pain, loss of function, mobility and subsequent loss of teeth, mobility and subsequent loss of dental implants, and recurrent infections. Additionally, deficient bone volume precludes adequate prosthetic reconstruction. Wound healing studies indicate that the most complete healing of oral and maxillofacial bone defects occurs when gingival epithelial and connective tissue cells are prevented from entering the bony defect.
There are several commercially available products that have been used successfully as guided tissue regeneration membranes, including those made from expanded polytetrafluoroethylene (PTFE), high density PTFE, bovine type I collagen, polylactide/polyglycolide co-polymers, calcium sulfate and even human skin. A review of the scientific literature indicates that no single ideal membrane material exists, but that each type of product has its own advantages and disadvantages.
An example of a current commercially available product employs a low-density expanded version of polytetrafluoroethylene (ePTFE) which presents a open-structure matrix to the gingival epithelial and connective tissue cells. This expanded version of PTFE is characterized by a low density of about 1.0 gm/cc or less and a porous, hydrophobic surface. In spite of the hydrophobic surface, soft tissue cells readily incorporate into the expanded matrix due to the open, porous structure of the material. While this connective tissue ingrowth is said to effectively prevent the migration of epilthelial cells, it presents a difficult problem to the patient and surgeon in the later stages of the regenerative procedure. After several weeks to several months, the non-absorbable low-density hydrophobic ePTFE barrier membrane must be removed. The incorporated cells and fibrous connective tissue make removal painful and traumatic to the patient and very time-consuming for the surgeon. The low-density open-matrix design of ePTFE devices also provides a location for the ingress of food particles, bacteria, and other foreign bodies which, in turn, create post-operative problems with the device such as inflammation, infection, wide exposure of the barrier material with wound dehiscence, and gingival recession. Any of these complications may require early removal of the barrier material, therefore compromising the treatment outcome. Low-density open-matrix or open-structure materials are generally soft and flimsy such that they will not mechanically support tissue above the defect during normal functional activities within the mouth causing a breakdown of the barrier's effectiveness. The articles described by Scantlebury, et. al. in U.S. Pat. Nos. 5,032,445 and 4,531,916 are such ePTFE devices.
Other products incorporate bio-absorbable polymer technology into their design. Such products are made from dense collagen matrices of human or bovine origin, which are broken down via hydrolysis and absorbed into the body fluids following several weeks to several months of implantation. While such devices eliminate the need for a second surgical procedure to remove them, some patients may exhibit a vigorous antigenic response to the devices which delays and often prevents the desired healing process within the defect, and may cause dehiscence of sutured wounds. Even in the absence of a specific antigenic response to implanted collagen, breakdown and resorption of these devices often results in generalized inflammatory cascade including neutrophil and macrophage activation. This foreign-body response also produces undesirable effects with regard to healing kinetics and pain. Bio-resorption time also varies significantly from patient to patient, presenting both patient and surgeon with an uncertainty regarding overall healing rate and pain management. Examples of collagen membranes in the literature are BioMend® and BioGide®. The articles described by Li in U.S. Pat. No. 5,206,028 and Geistlich in U.S. Pat. No. 5,837,278 are examples of such devices.
Synthetic polymers of lactide, glycolide and their various copolymers are also used as guided tissue regeneration barriers. These materials are biodegradable and offer the benefits of avoiding a surgical procedure for their removal. However, use of these materials results in inflammatory responses similar to those seen with naturally derived polymers such as collagen. In addition, the resorption profile may be unpredictable from patient to patient. These materials are also highly porous which renders them susceptible to bacterial colonization and contamination with foreign materials in the oral cavity in the event of exposure. A synthetic membrane barrier exhibiting similar characteristics is Vicryl® (polyglactin) periodontal mesh, Resolute® periodontal membrane described by Hayes et al, in U.S. Pat. No. 6,031,138 and Cytoplast® Resorb regenerative membrane.
Other products used as surgical membranes for the treatment of jaw and alveolar bone defects are human freeze-dried laminar bone and human freeze-dried dura mater obtained from human cadavers. These materials are bio-absorbable and osteoconductive, but carry a small but unknown risk of human disease transmission from donor to host. The risk of disease transmission precludes the use of this material by many surgeons and patients.
In an effort to provide a material with the biocompatibility and chemical inertness of PTFE but without the disadvantages of the porous open surface structure of expanded PTFE, a high density PTFE membrane material has been used and has achieved widespread clinical acceptance.
In U.S. Pat. No. 5,957,690 and U.S. Pat. No. 6,019,764 the use of a flexible high-density polytetrafluoroethylene (PTFE) sheet material was disclosed as a material suitable for guided tissue regeneration procedures. High density PTFE is substantially nonporous or microporous so as not to incorporate cells or attach to fibrous adhesions. By presenting a smooth surface to the biological materials, a high density PTFE barrier is easily inserted and removed following extended implantation periods. A similar high density PTFE barrier material is disclosed in U.S. Pat. No. 5,480,711. Examples of such products used for guided tissue regeneration include smooth and textured surface, hydrophobic high density PTFE such as Cytoplast®Regentex and TefGenFD®.
While high density PTFE medical barriers provide advantages over macroporous barriers, the smooth surface of the high density PTFE barriers sometimes leads to dehiscence of the soft tissue overlying the barrier. The dehiscence problem is caused in part by the fact that the smooth surface of high density PTFE will not incorporate cells and will not attach to fibrous adhesions as compared to expanded PTFE.
An additional clinical problem exhibited by high density PTFE is related to its hydrophobicity, or tendency to repel water. The chemical composition and resulting surface chemistry of a material determine its interaction with water. Hydrophobic materials have little or no tendency to adsorb water and water tends to “bead” on their surfaces in discrete droplets. Hydrophobic materials possess low surface tension values and lack active groups in their surface chemistry for formation of “hydrogen-bonds” with water. In the natural state, PTFE exhibits hydrophobic characteristics, which requires surface modification to render it hydrophilic. All previously disclosed products, whether constructed from expanded PTFE or high density PTFE have such hydrophobic characteristics.
It is well known in the art that biomaterial surfaces exhibiting hydrophobic characteristics are less attractive in terms of cell attachment. This is an advantage in some respects, as it prevents the ready attachment and migration of certain bacteria into the interstices of the material. However, in terms of interaction with host tissue, this characteristic may be less desirable and may contribute to dehiscence, or loss of soft tissue covering over the membrane during the course of healing. Dehiscence is a common clinical complication of guided tissue regeneration therapy, with an incidence of up to 60% according to the published literature. The clinical sequelae may indeed be serious, resulting in infection and failure of the procedure. The dehiscence phenomenon has been observed with both high density and expanded PTFE membrane devices, both of which to date have only been available with hydrophobic surfaces.
Although there are no reports of hydrophilic PTFE used in the construction of guided tissue regeneration membranes or similar implantable devices, hydrophilic, surface modified PTFE has a history of use as a filter in applications such as basic chemical and laboratory filtration, water purification, filtration of intravenous lines, blood oxygenators and extracorporeal hemofiltration devices.
U.S. Pat. No. 5,282,965 relates to a hydrophilic porous fluorocarbon membrane filter for liquids, which is used in microfiltration or ultrafiltration of liquids such as chemicals and water, and to a filtering device using said membrane filter. The filter is treated with low temperature plasma (glow discharge) to create a hydrophilic surface. Specifically this invention relates to a membrane filter for liquids, which is suitably used to filtrate chemicals for washing silicon wafers in semiconductor industries, and to a filtering device.
A hydrophilic semi-permeable PTFE membrane is disclosed in U.S. Pat. No. 5,041,225. This invention describes hydrophilic, semi-permeable membranes of PTFE and their manufacture, and further describes membranes suitable for use in body fluid diagnostic test strips and cell support members. In this instance, the intent of the hydrophilic membrane is to cover the target area of a diagnostic test strip with a semi-permeable membrane of a controlled pore size so that a fluid sample applied to such a membrane be applied in a controlled manner through the membrane to the underlying reagents. It should be noted that this invention discloses an in-vitro device and does not mention or anticipate use as a surgical implant.
Hydrophilic polymer membranes have been developed for use in the pharmaceutical industry as disclosed in U.S. Pat. No. 5,573,668 which describes a hydrophilic microporous membrane for drug delivery and a method for its preparation. Hydrophilicity is achieved by the application of a thin hydrophilic polymer shell, where the shell does not substantially alter the complex geometry of the membrane. Typically, drug delivery devices of non-resorbable polymers such as described in this patent are placed on the skin with adhesive, and are not surgically implanted.
Hydrophilic polymer membranes, which are biocompatible, antithrombogenic, and incorporate functional groups for immobilization of bioactive molecules are disclosed in U.S. Pat. No. 5,840,190. Specifically, this patent deals with membrane separators used in machines involved in the extracorporeal circulation of blood such as heart-lung machine oxygenators, hemofiltration units of dialysis machines, invasive blood gas sensors and artificial organs such as artificial pancreas and skin.
There are two methods described in this patent for fabrication of these surface modified membranes. “Method A” describes preparation of a casting solution containing the membrane forming polymer and then precipitating the casting solution in a bath containing the surface modifying polymer. “Method B” describes preparation of the casting solution containing the membrane forming polymer as well as the surface modifying polymer, and then precipitating the membrane from the casting solution in a coagulation bath. While this method may work with many polymers, including cellulose, cellulose acetate, polysulfone, polyamide, polyacrylonitrile, and polymethylmethacrylate, neither method is feasible with PTFE. Further, there is no mention of PTFE within the text or claims of this patent.
A method for coating a hydrophobic polymer so as to render said membrane hydrophilic is disclosed in U.S. Pat. No. 4,525,374. This method is said to be particularly for treating polypropylene or polytetrafluoroethylene in which the filter membrane is contemplated to have a pore size not larger than two (2) microns. The treating solution has Triethanolamine Dodecylbenzene Sulfonate (LAS) as the active ingredient. Treatment of expanded PTFE filters such as Poreflon® and GoreTex® are described in the context of filters for various chemical fluids such as intravenous fluids. There is no disclosure of use of said devices as a medical implant or guided tissue regeneration membrane.
A number of challenges are encountered in the design of the ideal GTR barrier. For example, the membrane must be dense enough to resist passage of unwanted cells such as epithelial cells and bacteria, yet be able to allow the passage of biological fluids, oxygen and nutrients required to sustain the viability of the regenerated tissue as well as the overlying tissue. The porosity of currently available products varies widely, from fully dense to over 30 microns in average pore size. According to the literature, those with larger pore size typically have a higher infection rate in clinical use. In contrast, the fully dense materials, while exhibiting superior characteristics in terms of infection resistance, are criticized due to the concern that they are unable to conduct the passage of nutrients in an efficient manner. Thus, there is a need for an improved membrane material of sufficient density to prevent the ingress of unwanted cells and bacteria, and yet be able to readily allow passage of biological fluids, molecules and oxygen.
A second major design issue involves the surface macrogeometry. The barrier membrane must be smooth enough to achieve a high degree of biocompatibility, yet must integrate well with the surrounding tissue to achieve clinical stability. Current products, with the exception of smooth surface dense PTFE membranes, rely on a complex three-dimensional surface structure to facilitate such tissue integration. A highly porous surface, while it is ideal for tissue ingrowth, presents problems with regard to bacterial contamination. An improved surface is needed which would encourage attachment of cells and tissues to achieve clinical stability without sacrificing the advantages of a smooth surface.
It is thus advantageous to provide a barrier device of dense, hydrophilic PTFE which will provide for selective cell repopulation of bone defects that does not allow the incorporation of cells or fibrous materials, has an improved hydrophilic surface for enhancement of cell attraction and attachment and for improved wetting by body fluids, is easy to remove after extended implantation periods, will not provide a location for contamination by foreign particles or bacteria, will not elicit a foreign-body inflammatory response, does not have the potential to transmit human infectious disease, is soft and supple such that compliance is similar to soft tissues, will facilitate retention of particulate grafting materials, and is convenient to use.